Title

Author

Defense Date

2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Michael MD Miles PhD

Abstract

A majority of Americans regularly consume alcohol, but the risk factors leading to excessive drinking and alcohol abuse are unevenly distributed throughout the population. Genetic differences can account for only 40-60% of this variability. While variations in ethanol preference drinking in rodent models have been reported, the neurobiological factors underlying these behaviors are still not completely understood. Thus, these studies were designed to determine behavioral and molecular factors associated with the initiation of ethanol drinking preference in an inbred mouse model. We harnessed the power of inter-individual variation of ethanol drinking within an inbred mouse strain to essentially eliminate genetic variability and focus on environmental factors. Our studies have characterized robust, persistent individual variability in ethanol intake in C57 mice using a two-bottle choice paradigm. Ethanol intake differences were not due to litter effects or differences in taste preference. Social rank nor basal anxiety phenotypes could account for ethanol preference. Based on the shared co-morbidity of anxiety and alcoholism, and that alcoholics report anxiety and stress reduction as major motivational factors for drinking, we used an ethologically-relevant social defeat model to investigate stress-influences on ethanol drinking. We found that social defeat has bidirectional effects on ethanol drinking. Mice with a low predilection for ethanol tend to increase drinking following social stress while high preference mice decrease drinking. Even though social defeat produced a measurable physiological response in mice, defeat stress did not alter anxiety measures in the light-dark box. Thus, the current findings did not fully support the tension-reduction hypothesis of alcoholism. In order to determine the molecular factors underlying these differences in ethanol preference drinking, we employed genome-wide expression profiling to identify gene networks altered in ethanol-preferring and ethanol-avoiding mice. Genes involved in synaptic vesicle release, glutamate and BDNF signaling were differentially altered in drinking mice. Following stress-influenced ethanol drinking, expression profiling identified transcripts involved in dopamine signaling, the extra-hypothalamic stress response and alterations in steroid and glucocorticoid synthesis. Most importantly, these expression studies and behavioral analysis following histone deacetylase inhibition may be the first to implicate epigenetic factors involving chromatin acetylation and/or methylation as contributing to environmental modulation of ethanol intake.